Research Focus

Proper control of metabolism is required for essentially every biological process. Altered metabolism at the cellular level contributes to many diseases including inborn errors of metabolism (the result of inherited genetic defects in metabolic enzymes that lead to chemical imbalances in children) and cancer. Our laboratory seeks to characterize these metabolic disorders, understand how they compromise tissue function, develop methods to monitor metabolism in vivo and design therapies to restore normal metabolism and improve health.

In cancer, we study how oncogenic control of metabolism supports tumor initiation and progression. In inborn errors of metabolism, we use metabolomics and genomics to identify new disease genes and deepen our understanding of metabolism’s role in human health. Our research is closely integrated with clinical activities in medical genetics, oncology and radiology, providing seamless opportunities to examine the relevance of our findings in patients.

Research Projects

Metabolic Pathways and Liabilities in Cancer Cells

Methods to Analyze Tumor Metabolism in Vivo

Inborn Errors of Metabolism and Other Mendelian Disorders

Metabolism and Development

Metabolic Pathways and Liabilities in Cancer Cells

Cancer cells use reprogrammed metabolic pathways to grow and resist stress encountered in the tumor microenvironment. These reprogrammed pathways facilitate malignant transformation and enable tumor progression. Identifying such pathways will allow us to better understand the biology of cancer and uncover new therapeutic targets. We use metabolomics, metabolic flux analysis, cell biology and animal models of cancer to study how tumor cells generate energy, build macromolecules and maintain redox balance. We seek to identify the processes, both intrinsic and extrinsic to the cancer cell, that affect tumor metabolism and to discover context-specific metabolic vulnerabilities that might provide a basis for new treatments.

As an example of our approach, we identified a new mechanism by which the MYC oncoprotein coordinates cell growth in small cell lung cancer (see figure – Huang et al., J Clin Invest 202). MYC transcriptionally activates many pathways, including well-known pathways of nucleotide and ribosome biogenesis, that need to be synchronized to culminate in cell proliferation. We discovered that MYC’s ability to activate guanosine triphosphate (GTP) synthesis is required to activate the ribosome program. These two processes are mechanistically linked by the small GTP-binding proteins GPN1 and GPN3, both of which are MYC targets and whose GTPase activity helps guide RNA Polymerase I to the rDNA to initiate ribosome biogenesis. Our findings provide an example of how MYC coordinates multiple biosynthetic programs in parallel to induce cell growth. Of note, reliance on this mechanism is prominent in chemotherapy-resistant small cell lung cancers, which are among the most treatment-refractory tumors but tend to display MYC activation. We report that these tumors can be treated in mice with clinically-available inhibitors of GTP synthesis.



Methods to Analyze Tumor Metabolism in Vivo

A major challenge is understanding which metabolic pathways promote cancer growth and progression in live tumors growing in a native microenvironment. We established clinical protocols combining multiparametric, preoperative imaging with intra-operative infusions of isotope-labeled nutrients (e.g., 13C-glucose) to address this challenge (Hensley et al, Cell 2016, Faubert et al, Nature Protocols 2022). Our approach allows us to assess metabolism in living, human tumors at multiple organ sites and compare isotope labeling features between tumor and adjacent tissues or between primary and metastatic tumors. This has allowed us to identify metabolic activities that could not have been predicted by experiments confined to cultured cells, and to determine which activities correlate with cancer progression and poor outcomes in patients. We have adapted these isotope labeling techniques to mouse models of cancer, allowing us to test hypotheses arising from observations in human cancer.

One discovery arising from this approach is that lactate provides a carbon source for some human tumors (see figure). Lactate, the end product of glycolysis, is traditionally viewed as a metabolic waste of cancer cells, and that its production and elimination from the cell are required to sustain energy production and redox balance. In some human non-small cell lung cancers, however, isotope labeling patterns indicate that lactate is taken up from the blood and provides a fuel for the tricarboxylic acid cycle (Faubert et al., Cell 2017). Interestingly, patients whose tumors display labeling hallmarks of lactate uptake have worse outcomes than patients whose tumors lack these hallmarks. Moving this observation into mouse models, we found that blocking lactate transport by melanoma cells suppresses metastasis, the leading cause of cancer-associated mortality (Tasdogan et al., Nature 2020). Altogether these findings demonstrate that we can use intra-operative isotope tracing in patients to identify unexpected metabolic activities that drive cancer progression.



Inborn Errors of Metabolism and Other Mendelian Disorders

We are interested in a large category of Mendelian diseases called inborn errors of metabolism (IEMs). These diseases are caused by pathogenic genomic variants (i.e. mutations) in genes encoding metabolic enzymes, nutrient transporters, and other components of the metabolic network. We are developing approaches to make it easier to recognize these disorders in patients by combining an unbiased analysis of the metabolome with genome/exome sequencing. Integrating metabolomics data with gene sequencing makes it possible to infer the impact of genomic variants of uncertain significance (see figure, DeBerardinis and Keshari, Cell 2022). Variants suspected of causing disease can then be subjected to functional analyses in cells or mice to understand how specific metabolic anomalies cause tissue dysfunction. We have used this approach to characterize rare Mendelian disorders and discover entirely new ones(Ni et al, Cell Reports 2019, Ni et al, Genetics in Medicine 2021) , with the long-term goal of developing better diagnostic techniques and treatments. Our clinical cohort of over 1,000 individuals provides a powerful resource to classify and explore metabolic variation in humans.



Metabolism and Development

It has long been known that metabolic demands evolve during different stages of mammalian embryogenesis, and that metabolic anomalies (e.g. nutritional deficiencies in the mother) can interfere with organogenesis. We want to decode the relationships between particular metabolic activities and particular developmental events, and IEMs provide a valuable starting point to this challenge. Because IEMs are monogenic disorders, all aspects of these diseases arise from mutation of a single node in the metabolic network. Some IEMs cause defects in organogenesis, indicating that particular metabolic activities are required for specific aspects of development. We are interested in malformations and defects in lineage commitment that arise downstream of human IEM mutations. As a system to study these mutations in mice, we developed an approach to observe metabolic activities across time and location during mid-gestation in utero (see figure, Solmonson et al, Nature 2022). This has allowed us to detect evolving, tissue-specific patterns of nutrient utilization in the developing embryo, and to pinpoint how IEMs perturb these patterns.

About Dr. DeBerardinis

Ralph DeBerardinis, cancer metabolism research

Ralph DeBerardinis earned a B.S. in biology from St. Joseph’s University and M.D. and Ph.D. degrees from the University of Pennsylvania. He performed his Ph.D. research on mammalian retrotransposons with Haig H. Kazazian, Jr. Dr. DeBerardinis was the first trainee in the combined residency program in pediatrics and medical genetics at The Children’s Hospital of Philadelphia (CHOP) and received several awards for teaching and clinical care. He ultimately achieved board certification in pediatrics, medical genetics and clinical biochemical genetics.

Dr. DeBerardinis performed postdoctoral research in Craig Thompson’s laboratory in the Penn Cancer Center from 2004 to 2007. He joined the faculty of the University of Texas Southwestern Medical Center in 2008 and joined the Children’s Medical Center Research Institute at UT Southwestern (CRI) in 2011. Dr. DeBerardinis serves as chief of Pediatric Genetics and Metabolism at UT Southwestern and director of the Genetic and Metabolic Disease Program in the CRI.

Dr. DeBerardinis received Outstanding Investigator Awards from the National Cancer Institute in 2017 and 2023, and was named an Investigator of the Howard Hughes Medical Institute in 2018. He received the Edith and Peter O’Donnell Award in Medicine from The Academy of Medicine, Engineering and Science of Texas in 2019 and the Paul Marks Prize for Cancer Research in 2021. Dr. DeBerardinis holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics, and he is a Sowell Family Scholar in Medical Research and a Robert L. Moody Faculty Scholar. In 2020, he was elected to the National Academy of Medicine.

Selected Research Publications

Kaushik, A.K., Tarangelo, A., Boroughs, L.K., Ragavan, M., Zhang, Y., Wu, C.Y., Li, X., Ahumada, K., Chiang, J.C., Tcheuyap, V.T., Saatchi, F., Do, Q.N., Yong, C., Rosales, T., Stevens, C., Rao, A.D., Faubert, B., Pachnis, P., Zacharias, L.G., Vu, H., Cai, F., Mathews, T.P., Genovese, G., Slusher, B.S., Kapur, P., Sun, X., Merritt, M., Brugarolas, J, and DeBerardinis RJ. (2022). In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. Science Advances 8:eabp8293. (PubMed)

Solmonson, A., Faubert, B., Gu, W., Rao, A., Cowdin, M.A., Mendez-Monte, I., Kelekar, S., Rogers, T.J., Pan, C., Guevara, G., Tarangelo, A., Zacharias, L.G., Martin-Sandoval, M.S., Do, D., Pachnis, P., Dumesnil, D., Mathews, T., Tasdogan, A., Pham, A., Cai, L., Zhao, Z., Ni, M., Cleaver, O., Sadek, H.A., Morrison, S.J., and DeBerardinis RJ. (2022). Compartmentalized metabolism supports midgestation mammalian development. Nature 604, 349-353. (PubMed)

Pachnis, P., Wu, Z., Faubert, B., Tasdogan, A., Gu, W., Shelton, S., Solmonson, A., Rao, A.D, Kaushik, A.K., Rogers, T.J., Ubellacker, J.M., LaVigne, C.A., Yang, C., Ko, B., Ramesh, V., Sudderth, J., Zacharias, L.G., Martin-Sandoval, M.S., Do, D., Mathews, T.P., Zhao, Z., Mishra, P., Morrison, S.J., and DeBerardinis RJ. (2022). In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors. Science Advances 8:eabn9550. (PubMed)

Huang, F., Huffman, K.E., Wang, Z., Wang, X., Cai, F., Yang, C., Cai, L., Shih, T., Zacharias, L.G., Chung, A., Yang, Q., Chalishazar, M.D., Ireland, A.S., Stewart, C.A., Cargill, K., Girard, L., Liu, Y., Ni, M., Xu, J., Wu, X., Zhu, H., Drapkin, B., Oliver, T.G., Byers, L.G., Gazdar, A.F., Minna, J.D., and DeBerardinis RJ. Guanosine triphosphate couples oncogenic MYC’s metabolic and ribosome programs. (2021). J Clin Invest 131:e139929. (PubMed)

Tasdogan, A., Faubert, B., Ramesh, V., Ubellacker, J.M., Shen, B., Solmonson, A., Murphy, M.M., Gu, Z., Gu, W., Martin, M., Kasitinon, S.Y., Vandergriff, T., Mathews, T.P., Zhao, Z., Schadendorf, D., DeBerardinis, R.J., and Morrison S,J. (2020). Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577,115-120. (PubMed)

Chen, P.H., Cai, L., Huffman, K., Yang, C., Kim, J., Faubert, B., Boroughs, L., Ko, B., Sudderth, J., McMillan, E.A., Girard, L., Chen, D., Peyton, M., Shields, M.D., Yao, B., Shames, D.S., Kim, H.S., Timmons, B., Sekine, I., Britt, R., Weber, S., Byers, L.A., Heymach, J.V., Chen, J., White, M.A., Minna, J.D., Xiao, G., and DeBerardinis, R.J. (2019). Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells. Mol Cell.76, 838-851. (PubMed)

Ni, M., Solmonson, A., Pan, C., Yang, C., Li, D., Notzon, A., Cai, L., Guevara, G., Zacharias, L.G., Faubert, B., Vu, H.S., Jiang, L., Ko, B., Morales, N.M., Pei, J., Vale, G., Rakheja, D., Grishin, N.V., McDonald, J.G., Gotway, G.K., McNutt, M.C., Pascual, J.M., and DeBerardinis, R.J. (2019) Functional Assessment of Lipoyltransferase- Deficiency in Cells, Mice, and Humans. Cell Rep. 27, 1376-1386. (PubMed)

Huang, F., Ni, M., Chalishazar, M.D., Huffman, K.E., Kim, J., Cai, L., Shi, X., Cai, F., Zacharias, L.G., Ireland, A.S., Li, K., Gu, W., Kaushik, A.K., Liu, X., Gazdar, A.F., Oliver, T.G., Minna, J.D., Hu, Z., and DeBerardinis, R.J. (2018). Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers. Cell Metab. 28, 369-382. (PubMed)

Faubert, B., Li, K.Y., Cai, L., Hensley, C.T., Kim, J., Zacharias, L.G., Yang, C., Do, Q.N., Doucette, S., Burguete, D., Li, H., Huet, G., Yuan, Q., Wigal, T., Butt, Y., Ni, M., Torrealba, J., Oliver, D., Lenkinski, R.E., Malloy, C.R., Wachsmann, J.W, Young, J.D., Kernstine, K., and DeBerardinis, R.J. (2017) Lactate Metabolism in Human Lung Tumors. Cell 171, 358-371. (PubMed)

Kim, J., Hu, Z., Cai, L., Li, K., Choi, E., Faubert, B., Bezwada, D., Rodriguez-Canales, J., Villalobos, P., Lin, Y-F., Ni, M., Huffman, K.E., Girard, L., Byers, L.A., Unsal-Kacmaz, K., Peña, C.G., Heymach, J.V., Wauters, E., Vansteenkiste, J., Castrillon, D.H., Chen, B.P.C., Wistuba, I,, Lambrechts, D., Xu, J., Minna, J.D., and DeBerardinis, R.J. (2017). CPS1 maintains pyrimidine pools and DNA synthesis is KRAS/LKB1-mutant lung cancer cells.  Nature 546, 168-172. (PubMed)

Hensley, C.T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., et al. (2016). Metabolic heterogeneity in human lung tumors. Cell 164, 681–694. (PubMed)

Jiang, L., Shestov, A.A., Swain, P., Yang, C., Parker, S.J., Wang, Q.A., Terada, L.S., Adams, N.D., McCabe, M.T., Pietrak, B., et al. (2016). Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258. (PubMed)

Selected Reviews and Commentaries

DeBerardinis, R.J. and Keshari, K.R. Metabolic analysis as a driver for discovery, diagnosis and therapy. (2022) Cell 85:2678-2689. (PubMed)

Faubert, B., Solmonson, A., and DeBerardinis, R.J. (2020). Metabolic reprogramming and cancer progression. Science. 368, eaaw5473. (Full Text)

DeBerardinis, R.J. and Chandel, N.S. We need to talk about the Warburg effect. (2020) Nature Metabolism 2:127-129. (PubMed).

DeBerardinis, R.J. (2020). Tumor Microenvironment, Metabolism, and Immunotherapy. New England Journal of Medicine  382, 869-871. (PubMed)

DeBerardinis, R.J. and Chandel, N.S. Fundamentals of cancer metabolism. (2016). Science Advances 2:e1600200. (https://pubmed.ncbi.nlm.nih.gov/27386546/)

Lab News


Lab Members

Divya Bezwada, M.S.

Ph.D. Student, Ruth L. Kirschstein NRSA Predoctoral Fellow

Eliot Blatt, Ph.D.

Postdoctoral Fellow

Bailey Brooks, B.S.

Research Technician

Feng Cai, metabolomics facility

Feng Cai, Ph.D.

Senior Research Scientist

Maggie Cervantes, B.S.

M.D./Ph.D Student

Hongli Chen, Ph.D

Senior Research Associate

Walter Chen, M.D., Ph.D.

Clinical Fellow, Neonatal-Perinatal Medicine

Dennis Dumesnil, M.S.

Research Technician

Wen Gu, Ph.D.

Postdoctoral Fellow

Bookyung Ko, metabolomics facility

Bookyung Ko, M.A., M.S.

Senior Research Associate

Michael Lee

M.D./Ph.D. Student

Xiangyi Li, M.D., Ph.D.

Senior Research Associate

Roger Liang

M.D./Ph.D. Student

Phyllis McDaniel, BSN, BBA, RN

Senior Research Nurse Coordinator

Phong Nguyen, Ph.D.

Postdoctoral Fellow

K. Celeste Oaxaca, M.S.

Research Assistant

Joao Santos Patricio, M.S.

Research Associate

Ashley Solmonson, Ph.D.

Ruth L. Kirschstein NRSA Fellow

Varun Sondhi, M.D., Ph.D.

Pulmonary and Critical Care Fellow

Jessica Sudderth, metabolomics facility

Jessica Sudderth, B.S.

Lab Manager/Research Scientist

Trevor Tippetts, Ph.D.

Postdoctoral Fellow

Aundrea Westfall, Ph.D.

Postdoctoral Researcher

Zheng Wu, Ph.D.

Postdoctoral Fellow

Chendong Yang, M.D., Ph.D.

Research Scientist

Lauren Zacharias, metabolomics facility

Lauren Zacharias, M.S.

Research Associate

Lindsey Boroughs, Ph.D.

Field Medical Scientist, Bristol-Myers-Squibb

Postdoctoral Fellow (2013-2016)

Ling Cai, Ph.D.

Assistant Professor, Quantitative Biomedical Research Center, UT Southwestern

Postdoctoral Fellow (2014-2016)

Mary Calvaruso, Ph.D.

Instructor, Department of Biotechnology and Biology, Biccocca University

Visiting Fellow (2013-2014)

Tzuling Cheng, Ph.D.

Senior Scientist, IDEAYA Biosciences

Postdoctoral Fellow (2009-2012)

Pei-Hsuan Chen, Ph.D.

Scientist, Vertex Pharmaceuticals

Ph.D. Student (2010-2015)

Daniel de los Santos

Medical Student, University of Vermont

Undergraduate Green Fellow (2014)

Robert Egnatchik, Ph.D.

Senior Research and Development Engineer, PepsiCo

Postdoctoral Fellow (2014-2016)

Brandon Faubert, Ph.D.

Assistant Professor, Department of Medicine, University of Chicago

Canadian Institutes of Health Research Fellow (2015-2021)

Rob Harris, Ph.D.

MSTP Student, UT Southwestern Medical School

M.D./Ph.D Student (2016-2021)

Lea Abou Haidar, M.D.

Pediatric Resident, UT Southwestern Medical Center

Postdoctoral Fellow (2022 – 2023)

Christopher Hensley, M.D., Ph.D.

Radiology Resident, University of Pennsylvania

M.D./Ph.D. Student (2011-2015)

Zeping Hu, Ph.D.

Assistant Professor, Tsinghua University

Assistant Professor (2012-2016)

Fang Huang, M.D., Ph.D.

Senior Visiting Scholar

Lei Jiang, Ph.D.

Assistant Professor, City of Hope

Assistant Instructor (2009-2017)

Akash Kaushik, Ph.D.

Senior Scientist, Internal Medicine Research Unit, Pfizer

Postdoctoral Fellow (2016-2022)

Sherwin Kelekar, Ph.D.

MSTP Student, UT Southwestern Medical School

M.D./Ph.D Student (2016-2022)

Jiyeon Kim, Ph.D.

Assistant Professor, University of Illinois at Chicago

Postdoctoral Fellow (2012-2018)

Sabin Kshattry

M.D./Ph.D. Student, UT Medical Branch

Undergraduate Green Fellow (2011)

Andrew Mullen, Ph.D.

Director of Operations, General Metabolics, LLC

Ph.D. Student (2008-2013)

Hien Nguyen, Ph.D.

Staff Scientist, University of Massachusetts Medical School

Postdoctoral Fellow (2011-2012)

Min Ni, Ph.D.

St. Jude Faculty

Associate Professor, Research (2014-2023)

Kristell Oizel, Ph.D.

Postdoctoral Fellow, Health Research Institute of the University of Nantes

Visiting Postdoctoral Fellow (2016-2017)

Panayotis Pachnis, MBBS, Ph.D.

Pediatrics Residency, UT Southwestern

Postdoctoral Fellow (2018-2021)

Pavel Pichurin, M.D., Ph.D.

Medical Geneticist, Mayo Clinic

Postdoctoral Fellow (2009-2011)

Alan Poole, M.D., Ph.D.

Assistant Professor, Pediatric Critical Care, UT Southwestern

Clinical Fellow (2016-2020)

Kartik Rajagopalan, M.D., Ph.D.

Pulmonary Critical Care Fellow, Columbia University Medical Center

M.D./Ph.D. Student (2010-2014)

Aparna Rao, MBBS, Ph.D.

Postdoctoral Scientist and Medical Oncologist, Peter MacCallum Cancer Centre

Postdoctoral Fellow (2018-2021)

Thomas Rogers, Ph.D.

Staff Scientist, Van Andel Institute

NCI Postdoctoral Fellow (2017-2022)

Tracy Rosales, Ph.D.

Field Application Scientist, ChemoMetec

Ph.D. Student, CPRIT Predoctoral Trainee (2017-2022)

Xiaolei Shi, Ph.D.

Physician-Scientist Training Program, Internal Medicine Residency, University of Minnesota

Ph.D. Student and HHMI International Student

Danny Vu, metabolomics facility

Danny Vu, Ph.D.

Scientist, St. Jude

Senior Research Scientist (2017-2023)

Ajla Wasti, M.D.

Pediatric Oncologist, Shaukat Khanum Memorial Cancer Hospital

Clinical Fellow (2012-2014)

Faith Zhang, M.D., Ph.D

Assistant Professor, Radiation Oncology, UT Southwestern Medical Center

Clinical Fellow (2018-2023)

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